Abstract Neurodegenerative diseases that involve the basal ganglia commonly lead to cognitive impairments. In this proposal, we hypothesize that the massive projections from the thalamic parafascicular (PF) and centromedian (CM) nuclei to the caudate nucleus and the putamen, respectively, are key pathways that regulate cognitive processing, and that lesion of these thalamostriatal systems produce selective attention-related cognitive impairments in behavioral flexibility, habit learning, and possibly other forms of cognition. The CM and PF provide functionally organized glutamatergic projections that target striatal projection neurons and interneurons (particularly cholinergic interneurons). Functional imaging data from human and monkey studies have shown that CM and PF neurons respond strongly to behaviorally significant sensory events. It was also shown that CM/PF inputs to the striatum regulate responses of striatal tonically active neurons (TANs; likely corresponding to cholinergic interneurons) to salient reward-related stimuli, and that inactivation of Pf disrupts performance in attention tasks. Because the CM/PF complex profoundly degenerates early in the course of Parkinson?s disease (PD) and Huntington?s disease (HD), a detailed knowledge of the role of the CM- and PF-striatal projections will help us to understand the importance of the degeneration of these nuclei in the development of cognitive impairments in PD and HD. In this pilot project, we will evaluate the behavioral consequences of selectively lesioning the CM- or Pf-striatal projections in monkeys, using an immunotoxin lesioning approach. These preliminary studies will set the foundation for the development of a future R01 proposal that will assess the contribution of the primate thalamostriatal system to cognition. A better knowledge of the role of this projection system in normal basal ganglia function is essential to gauge the importance of its degeneration in neurodegenerative diseases.